The pathogenesis of connective tissue abnormalities in human genetic disorders of connective tissue such as the Marfan and Ehlers-Danlos Syndrome and Homocystinuria is largely unknown. Their classification lacks precision in many cases because of the lack of well-defined biochemical abnormalities. This proposal seeks to identify abnormalities in collagen biosynthesis in these diseases with particular emphasis on collagen cross-linking. These diseases have all been reported to have increased soluble collagen on skin biopsy. It now appears that this finding may be due to a wide range of biochemical abnormalities such as failure to form normal fibrils, defective lysyl oxidase, the cross-linking enzyme, trapping of cross-linking intermediates, formation of unstable cross-links, cleavage of newly synthesized cross-links and increased collagen synthesis due to loss of feedback control. I propose to study collagen biosynthesis and cross-linking in these diseases in both fibroblast tissue culture and with an in vitro model of collagen cross-linking that more closely approximates biosynthesis of cross-links in vivo than other model systems. In addition, I propose to study the biosynthesis of human vascular collagen derived from human umbilical endothelial cells to determine if the vascular fragility observed in some of these syndromes may be related to abnormalities of vascular collagen. BIBLIOGRAPHIC REFERENCE: Siegel, R.C. and Lian, J.B.: Lysyl Oxidase Dependent Synthesis of a Collagen Cross-Link Containing Histidine. Biochem. Biophys. Res. Commun. 67:1353-1359, 1975.